Publications by authors named "Smrithi Salian"

12 Publications

  • Page 1 of 1

Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype-phenotype spectrum and functional impact on GPI-anchored proteins.

Clin Genet 2021 Nov 29;100(5):607-614. Epub 2021 Jul 29.

CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.

Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features. Flow cytometric analysis on patient fibroblasts showed a decrease in GPI-anchored proteins on the cell surface, supporting a lower residual activity of the mutant ARV1 as compared to the wildtype. A rescue assay through the transduction of lentivirus expressing wild type ARV1 cDNA effectively rescued these alterations. This study expands the clinical and molecular spectrum of the ARV1-related encephalopathy, confirming the essential role of ARV1 in GPI biosynthesis and brain function.
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http://dx.doi.org/10.1111/cge.14033DOI Listing
November 2021

PIGF deficiency causes a phenotype overlapping with DOORS syndrome.

Hum Genet 2021 Jun 2;140(6):879-884. Epub 2021 Jan 2.

Department of Pediatrics, CHU Sainte-Justine Research Center, University of Montreal, 3175, Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada.

DOORS syndrome is characterized by deafness, onychodystrophy, osteodystrophy, intellectual disability, and seizures. In this study, we report two unrelated individuals with DOORS syndrome without deafness. Exome sequencing revealed a homozygous missense variant in PIGF (NM_173074.3:c.515C>G, p.Pro172Arg) in both. We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis through flow cytometry analysis. We thus describe the causal role of a novel disease gene, PIGF, in DOORS syndrome and highlight the overlap between this condition and GPI deficiency disorders. For each gene implicated in DOORS syndrome and/or inherited GPI deficiencies, there is considerable clinical variability so a high index of suspicion is warranted even though not all features are noted.
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http://dx.doi.org/10.1007/s00439-020-02251-2DOI Listing
June 2021

De Novo KAT5 Variants Cause a Syndrome with Recognizable Facial Dysmorphisms, Cerebellar Atrophy, Sleep Disturbance, and Epilepsy.

Am J Hum Genet 2020 09 20;107(3):564-574. Epub 2020 Aug 20.

Sainte-Justine Hospital Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.
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http://dx.doi.org/10.1016/j.ajhg.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477011PMC
September 2020

A variant of neonatal progeroid syndrome, or Wiedemann-Rautenstrauch syndrome, is associated with a nonsense variant in POLR3GL.

Eur J Hum Genet 2020 04 6;28(4):461-468. Epub 2019 Nov 6.

Medical Genetics Division, Department of Pediatrics, Sainte-Justine University Hospital Center, Montreal, QC, Canada.

Neonatal progeroid syndrome, also known as Wiedemann-Rautenstrauch syndrome, is a rare condition characterized by severe growth retardation, apparent macrocephaly with prominent scalp veins, and lipodystrophy. It is caused by biallelic variants in POLR3A, a gene encoding for a subunit of RNA polymerase III. All variants reported in the literature lead to at least a partial loss-of-function (when considering both alleles together). Here, we describe an individual with several clinical features of neonatal progeroid syndrome in whom exome sequencing revealed a homozygous nonsense variant in POLR3GL (NM_032305.2:c.358C>T; p.(Arg120Ter)). POLR3GL also encodes a subunit of RNA polymerase III and has recently been associated with endosteal hyperostosis and oligodontia in three patients with a phenotype distinct from the patient described here. Given the important role of POLR3GL in the same complex as the protein implicated in neonatal progeroid syndrome, the nature of the variant identified, our RNA studies suggesting nonsense-mediated decay, and the clinical overlap, we propose POLR3GL as a gene causing a variant of neonatal progeroid syndrome and therefore expand the phenotype associated with POLR3GL variants.
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http://dx.doi.org/10.1038/s41431-019-0539-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080780PMC
April 2020

Further evidence for causation of ischiospinal dysostosis by a pathogenic variant in BMPER and expansion of the phenotype.

Congenit Anom (Kyoto) 2019 Jan 16;59(1):26-27. Epub 2018 May 16.

Department of Medical Genetics, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.

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http://dx.doi.org/10.1111/cga.12285DOI Listing
January 2019

Pycnodysostosis: Novel Variants in and Occurrence of Giant Cell Tumor.

J Pediatr Genet 2018 Mar 13;7(1):9-13. Epub 2017 Jul 13.

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.

Pycnodysostosis is an autosomal recessive skeletal dysplasia caused by pathogenic variants in the cathepsin K ( ) gene. We report seven patients from four unrelated families with this condition in whom we have identified three novel pathogenic variants, c.120 + 1G > T in intron 2, c.399 + 1G > A in intron 4, and c.148T > G (p.W50G) in exon 2, and a known variant, c.568C > T (p.Q190*) in exon 5 of . We present the clinical, radiographic, and molecular findings of all individuals with molecularly proven pycnodysostosis from the present cohort. We also report the occurrence of giant cell tumor in the skull of a patient with this condition.
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http://dx.doi.org/10.1055/s-0037-1604100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809170PMC
March 2018

Severe Form of Brachydactyly Type A1 in a Child with a c.298G > A Mutation in Gene.

J Pediatr Genet 2017 Sep 7;6(3):177-180. Epub 2017 Mar 7.

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.

Brachydactyly type A1 (BDA1) is characterized by short middle phalanges. We report the case of a child with a severe form of BDA1 with complete absence of the middle phalanges of all extremities. He had c.298G > A (p.D100N) mutation in gene.
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http://dx.doi.org/10.1055/s-0037-1599201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548527PMC
September 2017

Additional three patients with Smith-McCort dysplasia due to novel RAB33B mutations.

Am J Med Genet A 2017 Mar 27;173(3):588-595. Epub 2017 Jan 27.

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.

Smith-McCort dysplasia (SMC OMIM 615222) and Dyggve-Melchior-Clausen dysplasia (DMC OMIM 223800) are allelic skeletal dysplasias caused by homozygous or compound heterozygous mutations in DYM (OMIM 607461). Both disorders share the same skeletal phenotypes characterized by spondylo-epi-metaphyseal dysplasia with distinctive lacy ilia. The difference rests on the presence or absence of intellectual disability, that is, intellectual disability in DMC and normal cognition in SMC. However, genetic heterogeneity was suspected in SMC. Recently, RAB33B (OMIM 605950) has been identified as the second gene for SMC. Nevertheless, only two affected families have been reported so far. Here we present three SMC patients with four novel pathogenic variants in RAB33B, including homozygosity for c.211C>T (p.R71*), homozygosity for c.365T>C (p.F122S), and compound heterozygosity for c.48delCGGGGCAG (p.G17Vfs*58) and c.490C>T (p.Q164*). We also summarize the clinical, radiological, and mutation profile of RAB33B after literature mining. This report ascertains the pathogenic relationship between RAB33B and SMC. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38064DOI Listing
March 2017

Focal Dermal Hypoplasia with a Mutation p.E300* of Gene in a Male Infant.

Indian J Dermatol 2016 Nov-Dec;61(6):700

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.

Focal dermal hypoplasia is a rare disorder inherited in an X-linked dominant pattern and is usually antenatally lethal in males. We report a surviving male with postzygotic mutation p.E300* in exon 10 of gene with mosaicism, earlier reported in a female of Thai origin. This is the first report of this mutation from the Indian subcontinent.
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http://dx.doi.org/10.4103/0019-5154.193712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5122302PMC
December 2016

Variable presentation of Fraser syndrome in two fetuses and a novel mutation in FRAS1.

Congenit Anom (Kyoto) 2017 May;57(3):83-85

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, India.

We report on a consanguineous family with three pregnancies affected with Fraser syndrome. We note severe brachydactyly is a manifestation of Fraser syndrome and found a novel homozygous splice site variation c.3293-2A>T in FRAS1. We would like to highlight variable manifestations of Fraser syndrome and the presence of oligohydramnios in the antenatal period often makes prenatal diagnosis clinically challenging.
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http://dx.doi.org/10.1111/cga.12188DOI Listing
May 2017

Novel ALOX12B Mutation Identified in Parents following Single Nucleotide Polymorphism Microarray Testing of Banked DNA from a Fatal Case of Congenital Ichthyosis.

Indian J Dermatol 2016 Jan-Feb;61(1):122

Department of Medical Genetics, Kasturba Medical College, Manipal University, Manipal, Karnataka, India.

In genetically and phenotypically heterogeneous conditions like ichthyosis, it is clinically not possible to predict mutation in a specific gene. Sequential testing of all the causative genes is time consuming and expensive. In consanguineous families with autosomal recessive genetically heterogeneous disorders, it is possible to narrow down the candidate gene/genes by recognizing the regions of homozygosity by a single nucleotide polymorphism (SNP) array. Here, we present a fatal case of autosomal recessive severe congenital ichthyosis born to a consanguineous couple. Two candidate genes were recognized by SNP array on banked DNA of the subject. Sequencing of these candidate genes in parents found them to be carriers of the same variation, a novel heterozygous deletion of single nucleotide in exon 8 (c. 1067delT) of ALOX12B gene. The present case illustrates the utility of DNA banking, SNP array and testing of parents to arrive at a definitive molecular diagnosis, essential for genetic counseling, and prenatal testing.
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http://dx.doi.org/10.4103/0019-5154.174134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763652PMC
March 2016

Familial 7q11.23 duplication with variable phenotype.

Am J Med Genet A 2015 Nov 24;167A(11):2727-30. Epub 2015 Jun 24.

Department of Pediatrics, Narayana Multispecialty Hospital, Bangalore, India.

Chromosomal microdeletions and microduplications are known to cause variable clinical features ranging from apparently normal phenotype to intellectual disability, multiple congenital anomalies, and/or other variable clinical features. 7q11.23 region deletion is the cause for Williams-Beuren syndrome and duplication of same region 7q11.23 causes distinguishable clinical phenotype. Familial inheritance is known for both microdeletion and microduplication of 7q11.23 region. Here, we report a patient of paternally inherited 7q11.23 microduplication with developmental delay, macrocephaly, and structural brain malformations.
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http://dx.doi.org/10.1002/ajmg.a.37226DOI Listing
November 2015
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